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Tumour classification is based on the different characteristics of the tumour, such as primary site, biologic behavior, hormone or peptide secretions and symptoms. Tumour grade refers to the biologic aggressiveness and how likely the tumour is to spread. It is predictive of prognosis. This is based on what the pathologist detects, such as mitotic rate and Ki-67 index. It is important to note that low-grade NET can still metastasize. References: Klöppel G, et al. Ann Ny Acad Sci . 2004;1014:13-27. Rindi G, et al. Virchows Arch. 2007;451:757-762.

The WHO classification defines NETs by degree of tumor differentiation, taking into consideration specific clinicopathological features. 1[Kloppel2004, 16b, Table 1] The WHO classification system is based on the following criteria: 1[Kloppel2004, 25Table 7, Table 8] 2[Scholzen2000, 311c, 312b, 318c] Biological behavior (malignancy) Metastases Ki-67 index Ki-67 is a protein that correlates to cell division. A high Ki-67 index indicates a high rate of cell proliferation and is correlated with tumor proliferation. Angioinvasion Tumor size Histological differentiation Hormonal syndrome References: Kloppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci . 2004;1014:13-27. Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol . 2000;182(3):311-322.

WHO distinguishes the three classifications based on tumour size, metastases, Ki67 and biological behavior. Well-differentiated benign tumours typically indolent If less than 2 cm, they are not likely to have spread beyond the primary site Low-grade tumours on examination will usually demonstrate low to no mitotic activity in 10/HPFs with a Ki-67 of &lt; 2% Well-differentiated carcinoma are associated with malignant biologic behavior are associated with higher Ki-67 indexes and are more likely to metastasize. The primary tumour is typically greater than 2 cm Poorly differentiated carcinomas are most often associated with high mitotic activity, with Ki-67% of greater than 30%, and are aggressive. This slide is a general overview, in the following two slides specific examples of WHO classification will be reviewed. References: 1. Strosberg JR, Nasir A, Hodul P, Kvols L. GI Cancer Res. 2008; 2:113-125. 2. Klöppel G, Perren A, Heitz PU. Ann Ny Acad Sci. 2004;1014:13-27.

The WHO classification is clinically and prognostically useful for newly diagnosed neuroendocrine tumours as it takes into consideration the site of origin, the malignant potential and the functional activity of the tumour. Reference: Ong SL, et al. Pancreatology . 2009;9:583-600.

The incidence has been rising in the last three decades. This might be due to greater awareness, improved diagnostic capabilities, improved reporting to registries, or a change in nomenclature from carcinoid. With new successful treatments to control or slow the progression of the disease, the prevalence of cancer will increase. We will discuss these treatments in NET modules 3 and 4.

Neuroendocrine tumours can remain asymptomatic for a long period of time. Vague abdominal symptoms may be associated with primary tumour growth. These are not usually identified until they have metastasized and spread. Symptoms from syndromes secondary to hormone/peptide secretion such as diarrhea and flushing seen with carcinoid syndrome often does not appear until metastatic spread. Reference: Vinik A, et al. Pancreas . 2009 Nov;38(8):876-89.

Since the incidence is increasing and the prevalence is high, it is important for physicians to have NET in their differential diagnosis and suspect it over other more common ailments. It is also important to understand the vague difference in presentation For example, flushing of NET is slightly different than the flushing from menopause which is a typical misdiagnosis. Flushing with NET is unrelated to time or day, warmth, or perspiration Because CgA is usually elevated in NET, it should be ordered when there is even a small suspicion of NET. Reference: Peracchi M, Gebbia C, Basilisco G, et al. Eur J Endocrinol . 2003;148(1):39-43.

Depending on the results obtained from a workup, a patient’s NET is classified as local 5 , regional 5 , or advanced. 3,5,6 Treatment goals should be curative where possible, with the use of pharmacological management as necessary. 3 Local Regional NET The treatment goal for localized NETs is curative, which is most often accomplished with surgery. 3,7,8 Advanced NET The treatment goal for advanced NETs is also curative surgery if possible, followed by pharmacological treatment. 3,7

Radiation therapy (RT) involves the use of high-energy radiation from x-rays, gamma rays, neutrons, protons, and other sources to kill cancer cells and shrink tumors. 6 In general, the management of NETs with therapies, including radiation, is determined by the specific endocrine gland(s) involved, grade of differentiation, aggressiveness and stage of the tumor, amount of hormone produced, and specific patient needs. 3 PRRT represents a new advance in the treatment of NETs. It is based upon the presence of a greater number of somatotrophin release-inhibiting hormone receptors (also known as somatostatin receptors [SSTRs]) on NETs (compared with other tissues). 15 Radioembolization combines embolization with radiation therapy. This is done by injecting small radioactive beads into a main artery. The beads travel to the tumor and give off small amounts of radiation only at the tumor sites. 13

SSAs are currently approved for the relief of certain symptoms associated with symptomatic (functional) GI NETs and pNETs. 3,16,17 In addition, recent data from the PROMID clinical trial is being submitted to regulatory authorities. In patients with GI or Lung NETs, chemotherapy is considered a viable treatment option if not other treatments are feasible and the patient presents with unresectable liver metastases, symptomatic lung metastases, or metastasis to the regional lymph nodes. It is an option when no other treatments are feasible because of the poor efficacy and toxicity of chemotherapy. However, single-agent therapies and combination therapy with doxorubicin, 5-fluorouracil, dacarbazine, actinomycin-D, cisplatin, alkylating agents, etoposide, streptozotocin, and carboplatin have reported response rates ranging from 20% to 50%. 3 Systemic chemotherapy is recommended for patients with pNETs when they have unresectable liver or lung metastases. Trials using chemotherapeutic drugs including doxorubicin, streptozocin, 5-FU, temozolomide, and dacarbazine have established cytotoxic effects in pNETs. 3 Biological therapies include interferon. 18 Interferons are hormone-like proteins normally made by white blood cells to help the immune system fight infections. 18 Interferon-alpha is sometimes helpful in shrinking or slowing the growth of advanced NETs and improving symptoms of carcinoid syndrome. 19

Targeted therapies - these drugs are designed to attack some specific aspect of cancer cells. 20 A number of investigational therapies have shown preliminary evidence of activity in patients with advanced NETs, creating an opportunity to advance beyond traditional cytotoxic chemotherapy. 3,21 These include mTOR inhibitors (everolimus (AFINITOR)), as well as Tyrosine Kinase and VEGF pathway inhibitors (sunitinib, sorafenib, bevacizumab). 3,22,23,24 Pasireotide (SOM230), a multiligand somatstatin analogue, is currently in phase III development. 19,25,26

After randomization, patients received octreotide LAR 30 mg or placebo every 28 days until tumour progression, documented by CT or MRI, or death. Octreotide LAR 30 mg or placebo were administered by a study nurse or physician not involved in further patient care. Patients were blinded and all clinical assessments were performed without knowledge of the assigned treatment. During the study, additional antiproliferative therapy was not allowed. Post-study treatment in patients with tumour progression was at the discretion of the investigator. All patients will be followed-up until death. Tumour progression was evaluated using the WHO criteria. Importantly, CT and/or MRI scans were evaluated by a blinded central reader. In the event of progression, patients were unblinded to the investigator, who could then decide further treatment options for the patient. Once the study is finished, the investigator is unblinded with regard to the treatment. In patients who progressed while receiving placebo, octreotide LAR or a different treatment could have been administered. Patients enrolled in the PROMID study were treatment-naïve with locally inoperable or metastatic well-differentiated NETs with a midgut primary tumour without curative therapeutic options. Patients could have either a functioning or non-functioning tumour. Patients with symptoms of carcinoid syndrome and increased urinary 5-hydroxyindole acetic acid (5-HIAA) were classified as having a functioning tumour. Only those patients with carcinoid syndrome who tolerated flushing without intervention or responded to treatment with loperamide and/or cholestyramine in case of diarrhoea were included. Patients with a tumour of unknown origin were believed to have a midgut tumour if a primary within the pancreas, chest and elsewhere was excluded by multiphasic CT and/or MRI. Only those patients with measurable disease by CT or MRI were included. Progressive metastatic disease was not required for enrolment, however, all patients were required to demonstrate metastatic or inoperable disease measurable by CT or MRI. Although this does not necessarily mean that patients had progressive disease on entry, it would certainly have included patients with significant disease burden. Additional notes The term treatment-naïve means no treatment with, for example, drugs, cytotoxics, chemoembolization or radiotherapy, before study entry. It does not exclude surgical resection of the primary tumour. 69% of patients in the octreotide LAR 30 mg arm had resection of the primary tumour, but had liver metastases. 31% of patients had locally inoperable disease because of the size of the tumour or large lymph nodes. In total, 86% of patients had liver metastases. 75% of patients in the study had a hepatic tumour load of ≤10%. One of the strengths of the PROMID study is that in order to include a homogeneous patient population, only one group of tumours was included. Midgut NETs represent the largest subgroup of NETs, and by targeting these patients, the PROMID study addressed the question of the antiproliferative effects of octreotide LAR 30 mg in the largest homogeneous NET patient population.

Baseline characteristics of the patients were well balanced between treatment arms. The median time between diagnosis and randomization for the whole group was 4.3 months, however that seen in the placebo group was 3.3 months compared with 7.5 months in the octreotide LAR 30 mg group. Although the time since diagnosis appears to be nearly twice as long in the octreotide LAR 30 mg group, this is due largely in part to the inclusion of two patients in the octreotide LAR 30 mg treatment arm with a much longer time since diagnosis than patients in the placebo arm which skewed the results. About 40% of all patients had functioning tumours (carcinoid syndrome). 75% of patients had low tumour load (tumour load ≤10%). Tumour load ≤10% was seen in 32/42 (76%) patients in the octreotide LAR 30 mg group and 32/43 (74%) patients in the placebo group. The primary tumour had been removed in 66% of patients. Ki-67 was below 2% in 97.6% of octreotide LAR 30 mg recipients and in 93% of patients receiving placebo. CgA was elevated in 62% of the octreotide LAR 30 mg arm and in 70% of the placebo arm. These criteria indicate that, at randomization, all midgut NETs were comparable in their classification. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol . 2009;27:4656-4663.

In this study, 61.2% of patients had a non-functioning midgut NET and 38.8% of patients had a functioning tumour (carcinoid syndrome). Only those patients with mild carcinoid syndrome who tolerated flushing without intervention or responded to treatment with loperamide and/or cholestyramine in cases of diarrhoea were included. In patients with non-functioning NETs, there were 9/25 tumour progressions or tumour-related deaths in the octreotide LAR 30 mg group (TTP 28.8 months), compared with 24/27 events in the placebo group (TTP 5.91 months) [HR=0.25; P =0.0008]. There were fewer patients with functioning NETs than non-functioning NETs enrolled in the study. In patients with functioning NETs in the octreotide LAR 30 mg group, there were 11/17 events with a median TTP of 14.26 months. In the placebo group there were 14/16 events and a median TTP of 5.45 months (HR=0.23; P =0.0007). This analysis tells us is that while all patients in the PROMID study benefited from octreotide LAR 30 mg therapy, those patients with non-functioning NETs experienced the most benefit. This is a key finding of the PROMID study. Recent treatment guidelines are being updated to recommend octreotide LAR 30 mg as a therapeutic option in patients with non-functioning NETs which are progressive and metastatic.

RADIANT-3 is a prospective, double-blind, randomized, placebo-controlled phase III trial assessing the efficacy and safety of everolimus plus best supportive care vs. placebo plus best supportive care in patients with advanced pNET. This is the largest phase III randomized trial ever to be conducted in advanced pNET The trial accrued more rapidly than anticipated, meeting full enrollment in less than 2 years. In total, 410 patients were enrolled. The study was designed to detect a hazard ratio of 0.67 with 282 events needed to achieve 92% power. The primary endpoint of this trial was progression-free survival per investigator assessment. Secondary endpoints include safety and overall survival. Patients with advanced pNET and radiological progression within the preceding 12 months were randomized 1:1 to everolimus plus best supportive care versus placebo plus best supportive care. Best supportive care may include the use of somatostatin analogs. There are two stratification factors: Prior cytotoxic chemotherapy WHO performance status at baseline (0 vs. 1-2) Multi-phasic CTs and/or MRIs were performed every 12 weeks for response evaluation. Treatment continued until progression, unacceptable toxicity, or withdrawal. The patient may have discontinued participation in the study for any of the following reasons: Disease progression Adverse event(s) Abnormal laboratory value(s) Abnormal test procedure result(s) Protocol deviation Subject withdrew consent Lost to follow-up Administrative problems New cancer therapy Death At progression, patients were unblinded and if on placebo allowed to crossover to open label everolimus. Ninety-one percent (91%) of eligible patients who had progressed (148 out of 163) on the placebo arm received open label everolimus at the time of progression. Reference: Yao JC, Shah M, Ito T, et al. 35 th ESMO Congress 2010; Milan, Italy. Abstract #LBA9

Results of the PFS analysis as per central review were consistent with and support those generated from the local investigator assessment. Central review resulted in a hazard ratio of 0.34 and P -value of less than 0.0001, reflecting a 66% PFS risk reduction Median PFS values were also consistent with those reported for the local investigator assessment. The median PFS was 11.4 months with everolimus and 5.4 months with placebo. The prolongation in median PFS was 6.0 months. Reference: Yao JC, Shah M, Ito T, et al. 35 th ESMO Congress 2010; Milan, Italy. Abstract # LBA9

Median OS was not reached for either treatment group. The final analysis of OS will take place when approximately 250 deaths are reached. As expected when this trial was designed to allow crossover at the time of progression, no statistically significant difference was observed between the two treatment groups (HR= 1.05; 95% CI [0.71-1.55]; P =0.594). Crossover occurred for 148 (73%) of the 203 patients initially randomized to placebo prior to the data cut-off date. When considering placebo patients who had disease progression and were thus eligible for crossover, 148 out of 163 patients (91%) received open label everolimus. Subsequent use of other anti-neoplastic therapies after discontinuation of the study medication and crossover treatment with open label everolimus further confounded OS. There were a total of 101 deaths at the time of the data cut-off (February 28, 2010). Reference: Yao JC, Shah M, Ito T, et al. 35 th ESMO Congress 2010; Milan, Italy. Abstract #LBA9

This is a summary as presented by Dr Yao at the 35th European Society for Medical Oncologist Congress.

Median overall survival varies by primary site as well as stage of disease (SEER data excludes all benign malignancies). The primary tumour site was found to be a powerful predictor of survival duration ( P &lt; 0.001). In NET locations such as the lung, cecum, appendix, and small bowel there is little difference between local and regional spread in respect to poor prognosis. In contrast, prognosis is greatly affected in locations such as the colon, gastric, pancreas and rectum in relation to localized or regional NET. Overall, distant metastasis correlate with poor prognosis irrespective of the site of NET origin. In summary, disease site and disease spread alone are independent factors influencing prognosis but this varies dependent on location of NET. Reference: 1. Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063–3072.

4.
ClassificationTraditional Method NETs have been traditionally classified as foregut, midgut, or hindgut, depending on site of origin  Replaced by new tumor-based classification method developed by World Health Organization (WHO) 4

9.
Potential Reasons for Increased Incidence and Prevalence in NET• Exact reasons are unknown but may include: – Potential underdiagnoses and underreporting in the past – Improved diagnostic techniques – Increased awareness of NET in the community 9

17.
Importance of Raising the Index of Suspicion Incidence of NET is increasing  More prevalent than other cancers (ie, stomach, pancreas, esophagus) Associations between these symptoms suggest the presence of NET over more common ailments  Flushing with NET is unrelated to time or day, warmth, or perspiration  Hormone production differs from menopause, which is a typical misdiagnosis Elevated chromogranin A (CgA) is the generally accepted marker for NET  80% to 100% of NET, regardless of symptoms, secrete CgA 17Peracchi M, et al. Eur J Endocrinol. 2003;148(1):39-43.

20.
General NET Treatment Goals  Depending on the results obtained from a workup, a patient’s NET is classified as local, regional, or advanced.  Treatment goals should be curative where possible, with the use of pharmacological management as necessary.  General Treatment Goals: Local Regional NET The treatment goal for localized NETs is curative, which is most often accomplished with surgery. Advanced NET The treatment goal for metastatic tumors is also curative surgery if possible, followed by pharmacological treatment.

23.
Pharmacological Treatment of NET Several types:  Somatostatin analogues Currently approved for the relief of certain symptoms associated with symptomatic (functional) GI NETs and pNETs  Cytotoxic therapy GI and Lung NETs: An option when no other options are feasible because of the poor efficacy and toxicity. Single-agent and combination therapies with doxorubicin, 5-FU, dacarbazine, actinomycin-D, cisplatin, alkylating agents, etoposide, streptozotocin, and carboplatin have resulted in response rates from 20-50%. pNETs: Systemic chemotherapy is recommended for patients with unresectable liver or lung metastases. Trials using doxorubicin, streptozocin, 5-FU, temozolomide, and dacarbazine have established cytotoxic effects in pNETs.  Biological Treatment Interferon Hormone-like proteins normally made by white blood cells to help the immune system fight infections Sometimes helpful in shrinking or slowing growth of advanced NETs and improving symptoms of carcinoid syndrome

37.
Sunitinib Phase III Trial: SummaryInvestigator, algorithmic, and central analysis of PFS showed a mediandifference in PFS of 5.9 to 7.2 months (HR, 0.32-0.42) favoring sunitinib  The increase in PFS was not statistically significant  Though there is evidence of a clinically meaningful benefit, the magnitude of this benefit remains unclear due to the study being terminated early  These PFS results may be an overestimate because of early looks at the data and premature study terminationThe FDA did an additional analysis, and found a median PFS of 10.2 monthsfor sunitinib and 5.4 months for placebo; these data were used in the Sutentprescribing informationThere was no statistically significant improvement in OS(43% event rate; 69% crossover)There was an increased risk for serious AEs associated with sunitinib,including 2 deaths from cardiac failureMedian exposure to treatment and follow up were 4.6 months and 10.2months in the sunitinib arm and 3.7 months and 5.4 months in the placeboarm 40

38.
SummaryThe sunitinib trial and RADIANT-3 are both phase III,randomized, double-blind studies that assessed theeffects of treatment on PFS in patients with advancedpNET However, the trials differ substantially in design, patient population, and study conduct and, therefore, can not be directly compared 42